Arterial thrombosis is a common complication of many systemic diseases, including atherosclerosis,[unreadable] diabetes, cancer, and chronic inflammatory conditions. This proposal will test the hypothesis that CD36[unreadable] mediates platelet "hyper-reactivity" associated with systemic diseases, and thus contributes to arterial[unreadable] thrombosis. CD36 is a "pattern recognition" or scavenger receptor that recognizes ligands such as oxidized[unreadable] LDL, glycated proteins, and apoptotic cell membranes that are generated during pathological conditions. It is[unreadable] thus uniquely positioned to "sense" disease. Corollaries to the hypothesis are that platelets sensitized by[unreadable] CD36-ligand interactions may be resistant to anti-platelet therapies, and that levels of platelet CD36[unreadable] expression, perhaps under the influence of genetic polymorphisms, may contribute to human thrombotic risk.[unreadable] Three specific aims are proposed. The first will utilize in vitro assays of human platelet function to[unreadable] characterize the role of CD36 in platelet activation. Whether CD36 ligands, including oxidized phospholipids,[unreadable] apoptotic cells, advanced glycation end products, and anti-CD36 autoantibodies can sensitize platelets to[unreadable] activation by low concentrations of other agonists will be determined, as will mechanisms by which CD36[unreadable] initiates platelet signaling cascades. The second aim will characterize the pro-thrombotic role of CD36 in[unreadable] vivo using murine models. CD36 null mice crossed to an apoE null background will be used as a model of an[unreadable] atherogenic state, and CD36 nulls rendered hyperglycemic will be used as a model of diabetes. The effect[unreadable] of pharmacologic upregulation of CD36 will also be tested. The third aim will determine the potential role of[unreadable] human CD36 polymorphisms in athero-thrombosis. Variance in levels of human platelet surface CD36[unreadable] expression among individuals will be correlated with CD36 genotype, and associations of CD36 genotype[unreadable] and platelet CD36 expression with thrombotic risk and platelet resistance to aspirin and/or clopridogel will be[unreadable] determined.